Potassium Hydroxide → 5-(Methoxycarbonyl)pyridine-3-carboxylic acid

HRID 489616Notes

Reaction equation

HRID 489616 reaction equation
[N:1]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[CH:4]=[C:3]([C:12]([O:14][CH2:15]C)=[O:13])[CH:2]=1.[OH-].[K+]>C(O)C>[CH3:15][O:14][C:12]([C:3]1[CH:2]=[N:1][CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=1)=[O:13]

Participants

4

Reactant 2

HCID 14797Potassium HydroxideHCID 78340Diethyl pyridine-3,5-dicarboxylate

Product 1

HCID 198816385-(Methoxycarbonyl)pyridine-3-carboxylic acid

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of diethyl 3,5-pyridinedicarboxylate [prepared according to the procedure of J. C. Speelman and R. M. Kellogg, J. Org. Chem., 1990, 55 (2), pages 647-653; 64.19 g, 0.248 mol] in ethanol (650 mL) were added KOH pellets (14.56 g, 0.260 mol). The reaction mixture was stirred overnight at ambient temperature. Evaporation of solvent afforded a white solid that was rinsed with dichloromethane, and then dissolved in water. The aqueous solution was extracted with ether, and then acidified to pH 3. The resultant white precipitate was collected by filtration and dried to afford pyridine-3,5-dicarboxylic acid monomethyl ester (33.70 g). A portion of this material (10.00 g, 51.3 mmol) was dissolved in dry tert-butanol (300 mL) and treated sequentially with triethylamine (7.85 mL, 56.4 mmol) and diphenyl phosphoryl azide (11.5 mL, 53.4 mmol). The mixture was refluxed for 90 minutes, and then stirred at ambient temperature overnight. Solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried and concentrated. Chromatography on silica gel eluting with a mixture of pentane and ethyl acetate (3:1, v/v) gave 5-tert-butoxycarbonylamino-nicotinic acid ethyl ester (4.79 g). This ester was dissolved in methanol (45 mL) and treated with 1 N NaOH (54 mL, 54 mmol). After stirring 2 hours, volatiles were evaporated under reduced pressure and the residue was treated with 1 N HCl until the resultant slurry reached pH 3. The precipitate was collected by filtration, washed with water, and dried to afford 5-tert-butoxycarbonylamino-nicotinic acid (4.21 g): 1H NMR (300 MHz, DMSO-d6) δ 13.39 (br, s, 1H), 9.82 (s, 1H), 8.78 (d, J=2.5 Hz, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.45-8.50 (m, 1H), 1.50 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 152.7, 143.4, 143.2, 136.2, 126.3, 124.9, 80.0, 27.9; MS (ESI) m/z 239 (M+H).

Workup

  1. customEvaporation of solvent
  2. customafforded a white solid
  3. washthat was rinsed with dichloromethane
  4. dissolutiondissolved in water
  5. extractionThe aqueous solution was extracted with ether
  6. filtrationThe resultant white precipitate was collected by filtration
  7. customdried

Sources & evidence

ORD record
ord-ca1045b9687442149348bc599704db06
Source dataset
uspto-grants-2005_12
Patent number
US06977263B2

Reaction notes

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